Impact of chronic diseases on the periapical health of endodontically treated teeth: A systematic review and meta-analysis

Systemic diseases affecting the immune system can influence the body’s response time to endodontic treatment, potentially necessitating a longer duration for the complete resolution of existing infections when compared to healthy controls. This systematic review aims to evaluate the association between the presence of chronic diseases and periapical status after endodontic treatment through a systematic and comprehensive assessment of existing literature on this topic. The search strategy covered seven electronic databases and grey literature, encompassing articles published until October 2023. Two reviewers independently assessed potentially eligible studies based on the following criteria: Included were studies involving populations exposed to pre-existing chronic diseases who underwent endodontic treatment in permanent teeth. These studies evaluated periapical health status, making comparisons with healthy individuals. There were no language or publication date restrictions. Additionally, two reviewers independently extracted data regarding the characteristics of the included studies. The risk of bias was assessed using the Joanna Briggs Institute Critical Assessment Checklist. Meta-analysis was conducted using random effects models. The certainty of evidence was assessed using the GRADE tool. Twenty-three studies were included in the synthesis. Patients with diabetes were found to have about half the odds of having periapical health compared to non-diabetic patients (OR = 0.46; 95% CI = 0.30–0.70%; I2 = 58%) in teeth that underwent endodontic treatment. On the other hand, other systemic diseases like HIV, cardiovascular disease, and rheumatoid arthritis did not demonstrate significant differences concerning the outcome. In conclusion, diabetic patients showed a lower likelihood of maintaining periapical health. Conversely, patients with HIV, cardiovascular disease, and rheumatoid arthritis did not exhibit significant differences, although the existing evidence is still considered limited. It is crucial to manage these patients in a multidisciplinary manner to provide appropriate care for this population.


Introduction
Studies have highlighted the role of oral infections as contributing factors to the emergence of various systemic diseases [1,2].The process initiated by dental caries affects the dental structure, and when its progression occurs, the infection initially located in the dental pulp can spread to supporting structures, including bone tissue, thereby increasing the level of systemic exposure to these pathogens [3].If endodontic treatment is not performed, the root canal becomes a source of predominantly gram-negative bacteria [4], potentially leading to systemic repercussions.
Endodontic treatment is aimed at addressing both pulpal and periodontal tissues, requiring systematic chemical and mechanical cleaning and the sealing of canals and dental crowns.All these measures are necessary to ensure a favorable prognosis, preventing contamination and reinfection [5].However, it has been suggested that the systemic health condition may influence the outcome of endodontic treatment [6].Systemic diseases affecting the immune system can influence the body's response time to endodontic treatment, possibly requiring a longer time for the complete resolution of existing infections when compared to healthy controls [7].Patients with systemic diseases such as diabetes mellitus, hypertension, and coronary artery disease may have an increased risk of tooth extraction after non-surgical endodontic treatment [8].
A systematic review addressed the association between chronic diseases such as diabetes, cardiovascular disease, and the human immunodeficiency virus (HIV), and the outcomes of endodontic treatment.The results were inconclusive regarding the relationship between cardiovascular disease and diabetes with endodontic treatment outcomes.Additionally, no significant association was found between HIV-positive patients and endodontic treatment outcomes [9].However, it is important to note that this review was limited to only three databases and restricted its search until the year 2016, which precluded the conduct of a quantitative analysis through meta-analysis.Other reviews have addressed specific chronic diseases, but none aimed to assess the impact of chronic diseases more comprehensively [10,11].Furthermore, it is worth noting that new relevant studies have been published on this topic.Therefore, the need for a new systematic review with a comprehensive search strategy that includes a larger number of databases, as well as grey literature, to provide a more comprehensive and up-to-date overview is justified.It is also relevant to investigate whether other chronic diseases may influence the repair process following the endodontic treatment.
Therefore, this systematic review aims to evaluate the association between the presence of chronic diseases and the periapical status after endodontic treatment through a systematic and comprehensive assessment of existing literature on this topic.

Materials and methods
This present review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Checklist (PRISMA) guidelines (S1 Appendix) [12].

Eligibility criteria
The eligibility criteria applied to the studies included/excluded in this review were established according to the PECOS acronym, aiming to address the following focused question: "When compared to healthy individuals, can chronic diseases influence the outcome of endodontic treatment?"Population (P).Included studies involved populations that underwent endodontic treatment in permanent teeth.Studies where endodontic treatment was performed in deciduous teeth or where endodontic treatment was not performed were excluded.No studies were excluded based on the sex or ethnicity of the population.
Exposure (E).Included studies involved populations of interest exposed to pre-existing systemic chronic diseases, as confirmed through validated diagnoses.Chronic diseases were considered those that exhibit one or more of the following characteristics: they are permanent, leave residual disability, are caused by irreversible pathological changes, require special patient training for rehabilitation, or can be expected to necessitate long-term supervision, observation, or care [13].Studies where the exposure was an acute disease or where individuals were healthy were excluded.
Comparison (C).Included studies involved a comparison with healthy individuals.Studies where this condition was not established or those where the comparison was solely with subjects with chronic diseases, even if adequately controlled, were excluded.
Outcome (O).Studies were included that assessed the periapical health status using any standardized and validated metric, whether through clinical or radiographic evaluation.Excluded were studies where the outcome of interest was not assessed or where the assessment was not performed using the appropriate method.Studies that only evaluated the survival rate of endodontically treated teeth in the mouth, studies without imaging diagnosis, and studies that assessed the prevalence of periapical changes but did not quantify the number of teeth with a healthy apex were also excluded.

Study designs (S).
Included study designs encompassed cross-sectional, cohort, case-control, randomized clinical trials, non-randomized trials, or pseudo-randomized trials.Excluded were any descriptive studies, such as editorials, case reports, case series, expert opinions, and guidelines.

Sources of information and search strategy
Appropriate combinations of keywords and truncations were developed and adapted for the following databases: the Latin American and Caribbean Center on Health Sciences (LILACS), Cochrane Library, Embase, CINAHL, PubMed/Medline, Scopus, and Web of Science (S2 Appendix).Grey literature searches were also conducted through Google Scholar and Pro-Quest.The searches were initially conducted on November 8, 2021, and updated on October 25, 2023.Manual searches of the references of included articles were performed, and an expert on the team who did not participate in the reading phase was consulted to suggest any relevant publications on the topic.All references were managed using appropriate reference management software (EndNote 1 Web-Thomson Reuters, Philadelphia, PA), and duplicates were removed.

Selection process
The article selection process occurred in two phases: Phase 1: Two independent reviewers (B.M.M.A and T.K) read the titles and abstracts of the references retrieved by the search strategy in the databases.All articles that did not meet the eligibility criteria were excluded at this stage.The articles selected in phase 1 were read in full by the same reviewers, and the same eligibility criteria were applied (phase 2).All readings were conducted using the Rayyan website (https:// rayyan.qcri.org),enabling the blinding of the reviewers in all the assessments.In case of disagreement between the two reviewers that could not be resolved through discussion, a third team member (C.M.A) acted as a moderator, providing the tie-breaking vote.
To ensure calibration between the two reviewers, the Kappa coefficient was calculated, and the reading began only when the agreement value was > 0.7, indicating a good agreement.

Data collection process
The two reviewers (B.M.M.A and T.K) extracted relevant information from the included articles, such as study characteristics (author, publication year, country of origin, study design), sample characteristics (sample size, existing systemic disease, gender, average age), main results, and conclusion.
Similarly, when there was a disagreement that could not be resolved through discussion and mutual agreement between the reviewers, a third reviewer (C.M.A.) acted as a moderator to make the final decision.
If any data of interest to the research were missing or incomplete, two attempts were made to contact the first and last authors of the article to obtain unpublished information.Two email attempts were made, with a one-week interval between them.When there was no response, the article was excluded with a proper justification.

Data items
Data regarding the frequency of the event (outcome of success or failure of the endodontic treatment) were extracted from the included studies, along with the total sample size for both comparison groups.When the data were available only in graphical format, the web app Webplot Digitizer (https://apps.automeris.io/wpd) was used for data extraction.

Study risk of bias assessment
The risk of bias assessment was carried out using appropriate tools according to the epidemiological design of each study.For observational studies, the Joanna Briggs Institute tool was used for each type of study (cross-sectional studies and cohort studies).The risk of bias assessment was independently conducted by two reviewers who judged the included articles, marking each assessment criterion as "yes," "no," "unclear," or "not applicable."The risk of bias was classified as high when the study obtained 49% "Yes" scores, moderate when the study reached 50% to 69% "Yes," and low when the study achieved more than 70% "Yes" scores.
For the assessment of randomized clinical trials, the "Cochrane Collaboration tool for assessing risk of bias" was used.This tool evaluates seven different domains: random sequence generation, allocation concealment, participant and personnel masking, outcome assessor masking, incomplete outcome data, selective reporting of results, and other sources of bias.Each assessed domain was judged for possible risk of bias and classified as "high risk" or "low risk" of bias.
Non-randomized clinical studies were assessed using the ROBINS-I tool, which also evaluates seven domains: bias due to confounding, bias in the selection of participants in the study, bias in the classification of interventions, bias due to deviations from intended interventions, bias due to missing data, bias in the measurement of outcomes, and bias in the selection of the reported result.Each domain was classified as low, moderate, or serious risk of bias.
When there was insufficient data in the study that prevented a proper judgment, the risk of bias was considered "unclear."A third reviewer (C.M.A.) acted to resolve any disagreements that persisted even after a consensus meeting between the two reviewers.The robvis web app (https://www.riskofbias.info/welcome/robvis-visualization-tool)was used to generate figures.

Effect measures
The outcomes assessed in the included articles were reported as binary data.Therefore, the odds ratio (OR) was used as the effect measure to assess the association between individuals with systemic diseases and healthy individuals.

Synthesis methods
A random-effects meta-analysis was conducted using the statistical software RStudio version 1.2.1335 (Rstudio Inc, Boston, USA), with study weights determined by the Mantel-Haenszel method.Heterogeneity was calculated using the inconsistency index (I 2 ), and variance was estimated using the DerSimonian-Laird method.95% of confidence intervals (CI) were generated, and the significance level was set at 5%.Separate analyses were performed for each type of systemic disease.A minimum of three articles with the necessary data that met the eligibility criteria for quantitative synthesis was established for each systemic disease.
Articles that were not included in the meta-analysis were presented graphically using a bubble chart for categorical variables.For this, Python programming language was used, along with Matplotlib and NumPy libraries for data manipulation and graphical visualization.Each study was represented by a bubble, and positioned on the x and y axes to indicate the evaluated disease and the article's name, respectively.The color of the bubbles was used to differentiate treatment outcomes, while the size of the bubbles indicated the sample size of patients with the disease.The chart provided a clear and comparative visual representation of the results of the studies included in the systematic review.

Reporting bias assessment
A publication bias assessment using a funnel plot and Egger's test was planned.However, due to the limited number of available studies (n < 10), it was not possible to carry out this approach.To minimize the possibility of publication bias, a comprehensive search was conducted across various databases, including grey literature, as well as the LILACS database, which covers publications in languages other than English.

Certainty assessment
The level of certainty of the generated evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool [14].This tool classified the generated evidence into four levels of certainty: very low, low, moderate, and high, considering the following domains of evaluation: study limitations, inconsistency, indirect evidence, publication bias, imprecision, risk of bias, dose-response effect, and plausible confounding.

Study selection
A total of 2,817 articles were retrieved through the search strategy in the seven electronic databases, resulting in 1,731 references after duplicates were removed.After the analysis of titles and abstracts (phase 1), 39 articles were selected for full-text reading (phase 2).Following the full-text reading of the articles in phase 2, twenty articles were excluded (S3 Appendix).Four studies were included in the update search, resulting in 23 articles included for qualitative synthesis (Fig 1).No articles from grey literature were included, and none were found through manual reference searches or expert consultation.

Study characteristics
Among the included articles, all were written in English and originated from countries such as Brazil, Croatia, Spain, Finland, India, Iraq, Italy, Jordan, Portugal, the United Kingdom, Sweden, Turkey, and the United States.These articles were published between 1989 and 2021.The sample sizes of the studies ranged from 46 to 5494 participants, with average ages ranging from 18 to 84 years.The chronic diseases assessed included rheumatoid arthritis, diabetes, HIV, and heart diseases.The studies addressed disease diagnosis, post-treatment follow-up for up to 6 years, and the evaluation of lesion healing or repair.Detailed characteristics of the included studies can be found in Table 1.

Risk of bias in studies
Regarding the risk of bias in individual studies, five studies were identified as having a high risk of bias, and five studies had a moderate risk of bias (Fig 2).Most of these studies did not adequately control potential confounding factors, such as age, gender, type of endodontic treatment, post-treatment, and the variety of materials used.

Results of individual studies
The individual results of the included studies were categorized based on the underlying disease assessed.
Diabetes.Healthy patients exhibited a superior periapical condition, albeit without statistical significance [15,16].However, endodontic treatment proved effective in preserving treated teeth, even in type 2 diabetic patients with inadequate metabolic control.Periradicular lesions showed a slower healing and repair process in the diabetes group compared to the control group.Diabetic patients displayed a negative response after one year of follow-up.Nevertheless, in both groups, there was repair of the lesions, although the required time differed between them [17,18].A significantly higher healing rate was observed in the group of healthy patients compared to the diabetic group, but this disparity was evident only in the 6-month  follow-up [19].There was a slight tendency towards an increase in these lesions in diabetic patients who received insulin.Adequate glycemic control may not reduce the risk of developing these complications in type 2 diabetic patients [20].After the follow-up period, 68% of the cases showed success in endodontic treatment, although this percentage was reduced in diabetic patients with pre-existing lesions [21].Additionally, a higher prevalence of apical periodontitis and destruction of periapical and bone tissues was observed in the diabetic group compared to the control group [20,[22][23][24][25][26][27][28].A significant correlation was identified between patients' gender and treatment outcome, concluding that men with type 2 diabetes undergoing endodontic treatment were more likely to have residual lesions after treatment [29].On the other hand, women with long-term diabetes exhibited a higher proportion of endodontically treated teeth with periapical lesions compared to women with short-term diabetes and women without diabetes [30].HIV.No statistically significant difference was found in the treatment success between patients with and without HIV, indicating that a differentiated approach is not necessary for individuals infected with the HIV virus undergoing endodontic treatment [31].In the shortterm follow-up period (1 to 3 months) after treatment, no differences in treatment success were observed between patients with or without HIV.The adoption of a conventional approach for HIV patients can be used, dispensing with the use of prophylactic antibiotics [32].Although an improvement in the condition of apical periodontitis was observed in both HIV and non-HIV patients after treatment and one year of follow-up, there was no statistically significant difference in healing between them.These results suggest that additional specific approaches may not be imperative to achieve success or healing in HIV patients undergoing endodontic treatment [33].
Autoimmune diseases.It was observed that the prevalence of persistent apical periodontitis in at least one tooth was higher in the group of patients with rheumatoid arthritis compared to the control group.However, it is important to note that this difference did not reach statistical significance.These findings suggest a possible association between the presence of the autoimmune disease and the persistence of apical periodontitis, but further studies are needed to confirm this relationship and elucidate possible underlying mechanisms [34].The prevalence of apical periodontitis was significantly higher in the autoimmune diseases group (65.7%) compared to the control group (46.5%).Furthermore, the study revealed a significant association between smoking and apical periodontitis.Among the autoimmune disease subgroups, patients with rheumatoid arthritis had a lower likelihood of developing apical periodontitis compared to patients with inflammatory bowel disease.The patient's age and the use of tocilizumab were also identified as influential factors in the prevalence of apical periodontitis [35].
Various chronic diseases.A lower success rate in endodontic treatment was observed in patients with diabetes compared to healthy patients.Patients with cardiovascular diseases had relatively good success rates in endodontic treatment, with rates exceeding 80% for teeth with and without preoperative periapical lesions.In the case of other forms of immunosuppression, although success rates were around 78.6%, there was no significant difference compared to healthy individuals.Patients with DM were the only group with a significant difference in the success rate of endodontic treatment compared to patients without systemic diseases.However, further analysis revealed that, in addition to the presence of systemic disease, other dental factors also influenced the success of endodontic treatment.These dental factors were shown to be determinants in the decision-making and prognosis for clinical cases.Therefore, besides the systemic condition, it is essential to carefully consider individual dental factors when planning and performing endodontic treatment in these patients [6].

Results of the syntheses
The data from eleven studies were subjected to a meta-analysis with the aim of assessing the odds ratio for achieving the periapical index (PAI) scores � 2, indicating periapical health when assessed radiographically, in diabetic and non-diabetic patients with teeth that underwent endodontic treatment.
Patients with diabetes were found to have approximately half the odds of achieving PAI scores � 2, indicating a lower likelihood of maintaining periapical health compared to nondiabetic patients (OR = 0.46; 95% CI = 0.30-0.70%;I 2 = 58%) in teeth that underwent endodontic treatment (Fig 3).These results suggest that diabetes may have a negative impact on periapical health following endodontic therapy.
Regarding the articles that were not included in the meta-analysis, only studies that investigated patients with diabetes showed a difference in the periapical health of teeth treated endodontically compared to healthy individuals.The other chronic diseases did not show significant differences compared to healthy individuals (Fig 4).

Reporting bias
The funnel plot displayed no asymmetry, a finding supported by the non-statistically significant result from the Egger test (p = 0.728) (Fig 5).

Certainty of evidence
The certainty of the evidence was classified as very low for the association between diabetes and worsening of periapical health.The decrease in certainty of the evidence occurred due to the existence of only observational studies, the risk of bias present in the included articles, and the inconsistency between the estimates of the included studies, resulting in the presence of heterogeneity (Table 2).

Discussion
The repair of periapical lesions in endodontically treated teeth depends on the biological response of the host, with tissue healing being influenced by genetic factors and the overall systemic health of the individual.Therefore, it is crucial for the endodontist to be familiar with systemic factors that can affect the outcome of endodontic treatment, including the effects of systemic diseases on this outcome [36].The aim of this study was to systematically review the scientific literature on the impact of systemic diseases on periapical health in endodontically treated teeth.Patients with diabetes showed a lower probability of having periapical health compared to healthy patients.Other systemic diseases, such as HIV, cardiovascular disease, and rheumatoid arthritis, did not demonstrate significant differences in relation to the outcome.
Patients with diabetes have a reduced probability of maintaining periapical health following endodontic treatment when compared to healthy patients.These findings are consistent with previous studies that investigated the prevalence of periapical lesions in diabetic patients undergoing endodontic treatment, identifying a higher prevalence of radiolucent periapical lesions in diabetic patients compared to non-diabetic individuals [11,37].According to Saghiri et al. (2023), there are discrepancies in the internal structure of dentin in diabetic patients compared to healthy individuals.These discrepancies may have a direct impact on the outcome of endodontic treatment and, consequently, influence the periapical health after endodontic therapy [38].Despite the presence of moderate heterogeneity in the analysis, in this study, we chose to include only studies that used the Periapical Index (PAI) assessment in the meta-analysis [39].This approach allowed for the standardization of the assessment method  across various research studies, considering exclusively the count of teeth that demonstrated periapical health after endodontic therapy (PAI � 2).When considering patients with immunosuppression, whether due to HIV or the administration of immunosuppressive medications as seen in cases of rheumatoid arthritis, no significant difference in the periapical health was observed after undergoing endodontic therapy when compared to healthy individuals.In a study conducted by Laukkanen et al. (2019), which assessed patients with autoimmune cancer, or those using immunosuppressive medications, no significant difference was found in comparison to healthy individuals.Only three studies addressing the influence of HIV on periapical health after endodontic therapy were identified, and there are no recent studies on this topic.Regarding this specific disease, three articles were included in the analysis.All of them concluded that professionals did not need to adjust their approaches, as there was no difference in the healing and repair process of lesions when compared to groups without the disease.Both groups demonstrated a high success rate after the observation period.Additionally, the use of antibiotic prophylaxis was not shown to be necessary, as it did not exhibit significant effectiveness.
The relationship between cardiovascular diseases and periapical health is still a subject of controversy.According to Jakovljevic et al. (2020), there is a weak association between the presence of cardiovascular disease and periapical disease [40].On the other hand, in their investigation of the microbiota of periapical periodontitis, Minty et al. ( 2023) noted a correlation between hypertension and the increased severity of periapical lesions (higher scores on the PAI index) [41].In this review, only one study examined the impact of cardiovascular diseases on periapical health after endodontic therapy and did not find a significant association with periapical health [6].It is essential to conduct further research to investigate specific groups of cardiovascular diseases to better understand their relationship with periapical health after endodontic treatment.
It is important to highlight some limitations of the present study.The restriction to include only studies that used a standardized metric to assess the periapical health limited the number of eligible studies.Additionally, the included studies exhibited a moderate to high risk of bias, which reduces the certainty of the analyzed evidence.However, the study addresses a clinically relevant aspect since many patients seeking endodontic treatment may have systemic comorbidities.In the case of diabetic patients, it is crucial to inform them about the possibility of compromised periapical health compared to healthy patients.This underscores the importance of effective communication between healthcare professionals and patients to provide a wellinformed and appropriate treatment plan.For future research, it is recommended to conduct studies with rigorous methodologies, incorporating a more comprehensive identification and control of confounding factors.This will enhance the understanding of the impact of various systemic diseases on the periapical health of endodontically treated teeth.

Conclusion
Diabetic patients showed a lower likelihood of maintaining periapical health.Conversely, patients with HIV, cardiovascular disease, and rheumatoid arthritis did not exhibit significant differences, although the existing evidence is still considered limited.The intricate interplay between systemic health and periapical health underscores the importance of a multidisciplinary approach, especially for diabetic patients.Despite the lack of robust evidence supporting the impact of immunocompromised states and cardiovascular diseases on periapical health, it is crucial to manage these patients in a multidisciplinary manner to provide appropriate care for this population.

Table 2 . Summary of findings table. Question: When compared to healthy individuals, can chronic diseases influence the outcome of endodontic treatment? Certainty assessment of patients Effect Certainty № of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Chronic disease
a. Presence of studies with moderate and high risk of bias.b .Presence of heterogeneity in the analysis (I-squared = 58%).https://doi.org/10.1371/journal.pone.0297020.t002